System and method for determining deep brain stimulation parameters

ABSTRACT

A method of determining brain stimulation parameters includes applying Low Frequency Stimulation (LFS) to a contact of a multi-contact electrode implanted in a target structure in an individual&#39;s brain. Evoked Compound Activity (ECA) evoked in the target structure by the LFS is measured. A range of frequencies for delivering brain stimulation within a predetermined range based on a phase space extracted from the ECA is determined. Stimulation frequencies are applied to the contact of the multi-contact electrode within the determined range of frequencies. High Frequency Oscillations (HFO) evoked in the target structure by the applied stimulation frequencies within the determined range are measured. A frequency evoking HFO above a predetermined threshold is determined. The determined frequency is selected as a treatment frequency for the target structure.

CROSS-REFERENCE TO RELATED APPLICATION

This U.S. Non-Provisional patent application claims priority to U.S.Provisional Patent Application No. 63/066,141, filed on Aug. 14, 2020,and U.S. Provisional Patent Application No. 63/068,155, filed on Aug.20, 2020.

FIELD

The present disclosure relates to deep brain stimulation, morespecifically, to systems and methods for determining deep brainstimulation parameters.

BACKGROUND

Current brain stimulators are programmed by trial and error. This can beextremely time consuming. For example, programing can take hours persessions across multiple sessions, and follow up programming sessionsmay be needed. Therefore, there is a need for systems that can optimizethe programming parameters based on the response of the brain in anautomated and objective manner.

SUMMARY

Provided in accordance with aspects of the present disclosure is amethod of locating an implantation site in the brain including insertinga plurality of multi-contact electrodes into a region of a targetstructure in an individual's brain. High Frequency Stimulation (HFS) isapplied to a contact of a multi-contact electrode of the plurality ofmulti-contact electrodes. High Frequency Oscillations (HFO) induced inthe region of the target structure by the HFS are measured. EvokedCompound Activity (ECA) evoked in the region of the target structure bythe HFS is measured. It is determined if at least one of the HFO and theECA is above a predetermined threshold. If at least one of the HFO andthe ECA is above the predetermined threshold, a location of the contactof the multi-contact electrode is identified as a site for electrodeimplantation in the individual's brain.

In an aspect of the present disclosure, if the HFO and the ECA is belowthe predetermined threshold, a second high frequency stimulation isapplied to a second contact of the multi-contact electrode of theplurality of multi-contact electrodes. If no site for electrodeimplantation in the individual's brain is identified, the plurality ofmulti-contact electrodes is moved to a second region in the individual'sbrain.

In an aspect of the present disclosure, at least one electrode isconfigured for Deep Brain Stimulation (DBS) to the site for electrodeimplantation in the individual's brain.

In an aspect of the present disclosure, the target structure is theSubthalamic Nucleus (STN).

In an aspect of the present disclosure, measuring HFO and ECA isperformed intraoperatively.

In an aspect of the present disclosure, the HFS is greater than 100 Hz.

In an aspect of the present disclosure, the HFO includes an oscillationpattern greater than 300 Hz.

In an aspect of the present disclosure, the ECA includes a resonancepattern between 200-450 Hz.

In an aspect of the present disclosure, the plurality of multi-contactelectrodes is inserted into a brain of an individual having Parkinson'sDisease (PD).

Provided in accordance with aspects of the present disclosure is asystem for locating a site for electrode implantation in the brainincluding a plurality of multi-contact electrodes. The plurality ofmulti-contact electrodes is configured for insertion into a region of atarget structure in an individual's brain. A stimulating device is inelectrical communication with each of the plurality of multi-contactelectrodes. The stimulating device applies High Frequency Stimulation(HFS) to each of the plurality of multi-contact electrodes. Thestimulating device is configured to selectively apply the HFS to subsetof contacts of one multi-contact electrode of the plurality ofmulti-contact electrodes. A recording device is configured to measureHigh Frequency Oscillations (HFO) of Local Field Potentials induced inthe region of the target structure by the HFS. The recording device isconfigured to measure Evoked Compound Activity (ECA) evoked in theregion of the target structure by the HFS. A signal processing unit isin communication with the recording device. The signal processing unitdetermines if the at least one of the HFO and the ECA is above apredetermined threshold to identify a location of the one contact of themulti-contact electrode as a site for electrode implantation in theindividual's brain.

In an aspect of the present disclosure, a visualization unit visuallydisplays the measured HFO and ECA.

In an aspect of the present disclosure, a switching unit controls theHFS applied by the stimulating device. If the at least one of the HFOand ECA is below the predetermined threshold, the switching unit isconfigured to control the HFS to apply a second high frequencystimulation to a second contact of the multi-contact electrode of theplurality of multi-contact electrodes.

In an aspect of the present disclosure, the recording device isconfigured to measure HFO and ECA induced in Local Field Potentialsintraoperatively.

Provided in accordance with aspects of the present disclosure is amethod of determining brain stimulation parameters including applyingLow Frequency Stimulation (LFS) to a subset of contacts of amulti-contact electrode implanted in a target structure in anindividual's brain. Evoked Compound Activity (ECA) evoked in the targetstructure by the LFS is measured. A range of frequencies for deliveringbrain stimulation within a predetermined range based on a phase spaceextracted from the ECA is determined. Stimulation frequencies areapplied to the contact of the multi-contact electrode within thedetermined range of frequencies. High Frequency Oscillations (HFO)evoked in the target structure by the applied stimulation frequencieswithin the determined range are measured. A frequency evoking HFO abovea predetermined threshold is determined. The determined frequency isselected as a treatment frequency for the target structure.

In an aspect of the present disclosure, the target structure is theSubthalamic Nucleus (STN).

In an aspect of the present disclosure, measuring HFO and ECA isperformed chronically.

In an aspect of the present disclosure, the HFS is greater than 100 Hz.

In an aspect of the present disclosure, the LFS is less than 100 Hz.

In an aspect of the present disclosure, the selected frequency isgreater than 100 Hz.

In an aspect of the present disclosure, the selected frequency can beany frequency in the 100-200 Hz range.

In an aspect of the present disclosure, the measured HFO evoked in thetarget structure is between 200-450 Hz.

In an aspect of the present disclosure, the ECA includes a resonatingresponse above a predetermined threshold.

In an aspect of the present disclosure, if the ECA is below apredetermined threshold, a second LFS is applied to a second subset ofcontacts of the multi-contact electrode in a different location withinthe target structure than the contact of the multi-contact electrode.

In an aspect of the present disclosure, the multi-contact electrode isconfigured for Deep Brain Stimulation (DBS) of the target structure.

In an aspect of the present disclosure, the target structure is theSubthalamic nucleus (STN).

In an aspect of the present disclosure, the individual has Parkinson'sDisease (PD).

Provided in accordance with aspects of the present disclosure is asystem for determining deep brain stimulation parameters including atleast one multi-contact electrode configured for implanting in a targetstructure in an individuals' brain. A stimulating device is inelectrical communication with the at least one multi-contact electrode.The stimulating device is configured to apply Low Frequency Stimulation(LFS) or High Frequency Stimulation (HFS) to the at least onemulti-contact electrode. A recording device is configured to record atleast one of Evoked Compound Activity (ECA) evoked in the targetstructure by the LFS and High Frequency Oscillations (HFO) evoked in thetarget structure by the HFS. A signal processing unit is incommunication with the recording device. The signal processing unitdetermines a range of frequencies for delivering brain stimulationwithin a predetermined range based on a phase space extracted from theECA. The signal processing unit analyzes High Frequency Oscillations(HFO) evoked in the target structure by the applied stimulationfrequencies within the determined range. A parameter optimization unitdetermines a frequency evoking HFO above a predetermined threshold, andselects the frequency as a treatment frequency for the target structure.

In an aspect of the present disclosure, the stimulating device isconfigured to selectively apply the LFS or HFS to subset of contacts ofone multi-contact electrode of the plurality of multi-contactelectrodes.

In an aspect of the present disclosure, at least one of the stimulatingdevice, the recording device, the signal processing unit, and theparameter optimization unit are implanted in the individual's chest.

In an aspect of the present disclosure, an input/output (I/O) unit is inelectrical communication with the stimulating device, the recordingdevice, the signal processing unit, and the parameter optimization unit.

BRIEF DESCRIPTION OF THE DRAWINGS

The patent or application file contains at least one drawing executed incolor. Copies of this patent or patent application publication withcolor drawing(s) will be provided by the Office upon request and paymentof the necessary fee.

Various aspects and features of the present disclosure are describedhereinbelow with reference to the drawings wherein:

FIG. 1 is a block diagram of a system for locating an implantation sitein the brain according to aspects of the present disclosure;

FIG. 2 is a block diagram of a method for locating an implantation sitein the brain according to aspects of the present disclosure;

FIG. 3 is a block diagram of another method for locating an implantationsite in the brain according to aspects of the present disclosure;

FIG. 4 is a block diagram of an exemplary computer of a signalprocessing unit according to aspects of the present disclosure;

FIG. 5 is a block diagram of an implantable system for determining DBSparameters according to aspects of the present disclosure;

FIG. 6 is a block diagram of a method for determining DBS parametersaccording to aspects of the present disclosure;

FIG. 7 is a block diagram of another method for determining DBSparameters according to aspects of the present disclosure;

FIG. 8 displays recorded HFO evoked in the STN when a multi-contactelectrode is positioned in the STN and an absence of HFO when themulti-contact electrode is not positioned in the STN;

FIG. 9 displays recorded HFO and ECA at various HFS frequencies when themulti-contact electrode is positioned in the STN;

FIG. 10 displays recorded ECA for a LFS frequency compared with variousHFS frequencies; and

FIG. 11 illustrates DBS tuning of various HFS frequencies based on aphase of an ECA waveform.

DETAILED DESCRIPTION

As used herein, the term “distal” refers to the portion that is beingdescribed which is further from an operator (whether a human surgeon ora surgical robot), while the term “proximal” refers to the portion thatis being described which is closer to the operator. The terms “about,”substantially,” and the like, as utilized herein, are meant to accountfor manufacturing, material, environmental, use, and/or measurementtolerances and variations, and in any event may encompass differences ofup to 10%. Further, to the extent consistent, any of the aspectsdescribed herein may be used in conjunction with any or all of the otheraspects described herein.

Descriptions of technical features or aspects of an exemplaryconfiguration of the disclosure should typically be considered asavailable and applicable to other similar features or aspects in anotherexemplary configuration of the disclosure. Accordingly, technicalfeatures described herein according to one exemplary configuration ofthe disclosure may be applicable to other exemplary configurations ofthe disclosure, and thus duplicative descriptions may be omitted herein.

Exemplary configurations of the disclosure will be described more fullybelow (e.g., with reference to the accompanying drawings). Likereference numerals may refer to like elements throughout thespecification and drawings.

In aspects of the present disclosure, modulations in local fieldpotentials (LFP) induced by electrical stimulation of the subthalamicnucleus (STN), such as in Parkinson's disease (PD) patients, undergoingdeep brain stimulation (DBS) are employed. The systems and methodsdescribe herein optimize frequency and other parameters to increase theeffectiveness of DBS by locating ideal implantation sites andcalibrating treatment parameters on an individual basis. The systems andmethods described herein deliver electrical stimulation to the brain andrecord the response of the brain before, during and after stimulation.Based on the measured electrophysiological markers in response to thestimulation, the method and system fine tunes its parameters. Sincemovement and other psychiatric disorders are a network disease, oneadvantage of the systems and methods described herein is that they probethe state of the network with stimulation and then adapt the stimulationparameters to the response signal in a closed-loop fashion.

In the STN, therapeutic high-frequency stimulation (130-180 Hz) induceshigh-frequency oscillations (˜300 Hz, HFO) similar to those observedwith pharmacological treatment. Along with HFOs, evoked compoundactivity (ECA) after each stimulation pulse was identified. While ECAwas observed in both therapeutic and non-therapeutic (20 Hz)stimulation, the HFOs were induced only with therapeutic frequencies andthe associated ECA were significantly more resonant. The relative degreeof enhancement in the HFO power was related to the interaction ofstimulation pulse with the phase of ECA.

High-frequency STN-DBS tunes the neural oscillations to theirhealthy/treated state, similar to pharmacological treatment, and thestimulation frequency to maximize these oscillations can be inferredfrom the phase of ECA waveforms of individual subjects. The induced HFOscan, therefore, be utilized as a marker of successful re-calibration ofthe dysfunctional circuit generating PD symptoms.

As described in more detail below, high-frequency stimulation (HFS)exerts its therapeutic effect by modulating oscillatory activity in theSTN, similar to the effect of pharmaceutical treatment.

It is anticipated that the systems and methods described herein may beapplied to movement disorders such as Parkinson's disease, essentialtremor, Tourette's syndrome, epilepsy, dystonia, psychiatric/cognitivedisorders such as obsessive-compulsive disorder, severe depression,Alzheimer's dementia, and bipolar disorder.

It is anticipated that the systems and methods described herein may beapplied to target brain structures such as the STN, globus pallidus(internal and external), thalamus, cortex, substantia nigra (parsreticulata and pars compacta), and the pedunculopontine nucleus.

The phrase “chronic electrode” refers to a multi-contact electrode, suchas a DBS electrode, that has been surgically implanted in anindividual's brain. The chronic electrodes described in more detailbelow may each have individually activatable contacts at differentlocations similar to that of the multi-contact electrodes describedherein. Each contact of each choric electrode/multi-contact electrodemay be controlled to deliver DBS based on a variety of parameters thatare specially adjusted to account for an individuals personalized brainresponses.

Referring to FIG. 1, a system 100 for locating a site for electrodeimplantation in the brain includes a plurality of multi-contactelectrodes 101. The plurality of multi-contact electrodes 101 isconfigured for insertion into a region of a target structure 102 in anindividual's brain. Each multi-contact electrode 101 extends to adifferent geographic region along a distinct anatomic track (e.g., atdifferent depths with respect to the individual's skull). A plurality ofcontacts 103 are spaced apart from each other along a length (e.g.,along a proximal to distal length) of each multi-contact electrode 101.

A stimulating device 104 is in electrical communication with each of theplurality of multi-contact electrodes 101. The stimulating device 104applies High Frequency Stimulation (HFS) to each of the plurality ofmulti-contact electrodes 101. The HFS may be greater than 100 Hz (e.g.,from 100 Hz to 200 Hz).

The stimulating device 104 is configured to selectively apply the HFS toa subset of contacts 103 of one multi-contact electrode 101 of theplurality of multi-contact electrodes. A recording device 105 isconfigured to measure High Frequency Oscillations (HFO) evoked in theregion of the target structure 102 by the HFS. The recording device 105is configured to measure Evoked Compound Activity (ECA) evoked in theregion of the target structure 102 by the HFS.

A signal processing unit 106 is in communication with the recordingdevice 105. The signal processing unit 106 determines if at least one ofthe HFO and the ECA is above a predetermined threshold to identify alocation of the one contact 103 of the multi-contact electrode 101 as asite for electrode implantation in the individual's brain.

A visualization unit 107 visually displays the measured HFO and ECA. Thevisualization unit 107 may individually display HFO or ECA evoked byeach contact 103 of each multi-contact electrode 101. Thus, aneurosurgeon or clinical expert 108 can visually identify HFO/ECA evokedby each individual contact 103.

According to an aspect of the disclosure, a switching unit controls 109the HFS applied by the stimulating device 104. If the at least one ofthe HFO and ECA is below the predetermined threshold, the switching unit109 is configured to control the stimulating device 104 to apply asecond HFS to a second subset of contacts 103 of the multi-contactelectrode 101 of the plurality of multi-contact electrodes.

The system 100 described with reference to FIG. 1 is configured tomeasure HFO and ECA intraoperatively. After one or more sites forelectrode implantation in the individual's brain are identified, anelectrode (i.e., a chronic electrode) is surgically implanted in each ofthe one or more sites for long term DBS.

FIG. 2 is a block diagram of a method 200 for locating an implantationsite in the brain that may be employed by the system 100.

Referring to FIG. 2, method 200 includes applying HFS (step 201),measuring evoked response amplitude (step 202) and estimating bandpowerfor the specified high-frequency range (step 203). The method includesdetermining if a maximum signal strength is received (step 204). If amaximum signal strength is received then an implant is implanted (step205). If a maximum signal strength is not received then a decision ismade to move to another location (step 206).

Referring to FIGS. 1 and 3, another method of locating an implantationsite in the brain 300 that may be employed by the system 100 isdescribed. Method 300 includes inserting a plurality of multi-contactelectrodes into a region of a target structure in an individual's brain(step 301). The multi-contact electrodes can be extended through burrhole formed in the individual's skull.

HFS is applied to a contact of a multi-contact electrode of theplurality of multi-contact electrodes (step 302). High FrequencyOscillations (HFO) evoked in the region of the target structure by theHFS are measured (step 303). Evoked Compound Activity (ECA) evoked inthe region of the target structure by the HFS is measured (step 304). Itis determined if at least one of the HFO and the ECA is above apredetermined threshold (step 305). If at least one of the HFO and theECA is above the predetermined threshold, a location of the contact ofthe multi-contact electrode is identified as a site for electrodeimplantation in the individual's brain (step 306).

Each multi-contact electrode 101 may extend along a distinct anatomictrack and distal-ends thereof may end at various depths within anindividual's brain. Each multi-contact electrode 101 may includenumerous contacts 103 positioned along a length thereof. Each contact103 may selectively and individually receive an electrical stimulation(LFS or HFS) to test various depths along various tracks of the user'sbrain. Thus, by individually applying electrical stimulationintraoperatively, an ideal track and an ideal depth may be identified.For example, with reference to FIG. 1, Track 3 may entirely miss thetarget structure, Track 2 may align with a periphery of the targetstructure, while Track 3 aligns with a central region of the targetstructure. Further, a distal-most contact (i.e., contact 1) of Track 1may evoke a maximum ECA and HFO. Thus, the position of contact 1, alongthe Track 1 multi-contact electrode would be identified as a desiredsite for electrode implantation in an individual's brain. The implantedelectrode, as described in more detail below, can then be calibrated byadjusting the specific parameters thereof, to maximize effectiveness ofDBS on an individual basis. As described in more detail below, parameteradjustments can be made to account for an individual's personalizedbrain response and underlying structural or electrochemical variations.The combination of idealized electrode placement and idealized parametersettings maximizes treatment effectiveness of DBS. Further, theparameter adjustments can be periodically adjusted to account forchanges within an individual's underlying disease state progression,anatomical changes occurring over time, or electrochemical changesoccurring over time.

If the HFO or the ECA is below the predetermined threshold, a secondhigh frequency stimulation is applied to a second subset of contacts ofthe multi-contact electrode of the plurality of multi-contactelectrodes. If no site for electrode implantation in the individual'sbrain is identified, the plurality of multi-contact electrodes is movedto a second region in the individual's brain. For example, If none ofthe multi-contact electrodes are found to evoke a supra-threshold HFO orECA, the multi-contact electrodes can be advanced further into theindividual's brain on a millimeter by millimeter basis until a desiredHFO/ECA is evoked by at least one contact.

In an aspect of the present disclosure, the HFS is greater than 100 Hz.

In an aspect of the present disclosure, the HFO includes an oscillationpattern between 200-450 Hz.

In an aspect of the present disclosure, the ECA includes a resonancepattern above a predetermined threshold (see, e.g., FIG. 11 described inmore detail below).

FIG. 4 is a block diagram of an exemplary computer 400 of a signalprocessing unit 106 of FIG. 1 according to an aspect of the presentdisclosure.

Referring to FIG. 4, the signal processing unit 106 may include aprocessor 401 connected to a computer-readable storage medium or amemory 402 which may be a volatile type memory, e.g., RAM, or anon-volatile type memory, e.g., flash media, disk media, etc. Theprocessor 401 may be another type of processor such as, withoutlimitation, a digital signal processor, a microprocessor, an ASIC, agraphics processing unit (GPU), field-programmable gate array (FPGA), ora central processing unit (CPU).

In some aspects of the disclosure, the memory 402 can be random accessmemory, read-only memory, magnetic disk memory, solid state memory,optical disc memory, and/or another type of memory. The memory 402 cancommunicate with the processor 401 through communication buses 403 of acircuit board and/or through communication cables such as serial ATAcables or other types of cables. The memory 402 includescomputer-readable instructions that are executable by the processor 401to operate the signal processing unit 106. The signal processing unit106 may include a network interface 404 to communicate with othercomputers or a server. A storage device 405 may be used for storingdata. The signal processing unit 106 may include one or more FPGAs 406.The FPGA 406 may be used for executing various machine learningalgorithms. A display 407 may be employed to display data processed bythe signal processing unit 106.

The signal processing unit 106 described with reference to FIGS. 1 and 4is substantially the same as the signal processing unit 506 describedwith reference to FIG. 5 below unless otherwise indicated, and thusduplicative descriptions may be omitted herein. For example, the signalprocessing unit 506 illustrated in FIG. 5 may have substantially thesame hardware configuration as that of the signal processing unit 106illustrated in FIG. 1. The switching unit 509, recording device 505, andstimulating device 504 described with reference to FIG. 5 below aresubstantially the same as the switching unit 109, recording device 105,and stimulating device 104 described with reference to FIGS. 1 to 3unless otherwise indicated, and thus duplicative descriptions may beomitted herein.

Referring to FIG. 5, a system 500 for determining deep brain stimulationparameters includes at least one multi-contact electrode 501 configuredfor implanting in a target structure 502 in an individuals' brain. Themulti-contact electrode 501 may be a chronically implanted electrode, asdescribed in more detail below. The stimulating device 504 is inelectrical communication with the at least one multi-contact electrode501. The stimulating device 504 is configured to apply Low FrequencyStimulation (LFS) (e.g., less than 105 Hz) or High Frequency Stimulation(HFS) (e.g., from 100 Hz to 200 Hz) to the at least one multi-contactelectrode 501.

According to an aspect of the disclosure, the switching unit 509controls the HFS applied by the stimulating device 504. If the at leastone of the HFO and ECA is below the predetermined threshold, theswitching unit 509 is configured to control the stimulating device 504to apply a second HFS to a second subset of contacts 503 of themulti-contact electrode 501 of the plurality of multi-contactelectrodes.

The recording device 505 is configured to record at least one of EvokedCompound Activity (ECA) evoked in the target structure 502 by the LFSand High Frequency Oscillations (HFO) evoked in the target structure 502by the HFS. The signal processing unit 506 is in communication with therecording device 505. The signal processing unit 506 determines a rangeof frequencies for delivering brain stimulation within a predeterminedrange based on a phase space extracted from the ECA (see, e.g., FIG.11). The signal processing unit 506 analyzes High Frequency Oscillations(HFO) evoked in the target structure 502 by the applied stimulationfrequencies within the determined range. A parameter optimization unit511 determines a frequency evoking HFO above a predetermined threshold,and selects the frequency as a treatment frequency for the targetstructure.

The stimulating device 504 is configured to selectively apply the LFS orHFS to one contact 503 of one multi-contact electrode 501.

In an aspect of the present disclosure, an input/output (I/O) unit 512is in electrical communication with the stimulating device 504, therecording device 505, the signal processing unit 506, and the parameteroptimization unit 511.

At least one of the stimulating device 504, the recording device 505,the signal processing unit 506, and the parameter optimization unit 511are implanted in the individual's chest. For example, a processingsubsystem 512 including the signal processing unit 506, the parameteroptimization unit 511 and the I/O unit 512 may be implanted in thepatient's chest.

The processing subsystem 512 can control the implanted multi-contactelectrodes 501 for DBS.

Referring to FIGS. 5 to 7, a method of determining brain stimulationparameters includes applying Low Frequency Stimulation (LFS) (e.g., lessthan 105 Hz) to a contact of a multi-contact electrode implanted in atarget structure in an individual's brain. Evoked Compound Activity(ECA) evoked in the target structure by the LFS is measured.

A range of frequencies for delivering brain stimulation within apredetermined range based on a phase space extracted from the ECA isdetermined. Stimulation frequencies are applied to the contact of themulti-contact electrode within the determined range of frequencies. HighFrequency Oscillations (HFO) of Local Field Potentials evoked in thetarget structure by the applied stimulation frequencies within thedetermined range are measured. A frequency evoking HFO above apredetermined threshold is determined. The determined frequency isselected as a treatment frequency for the target structure.

In an aspect of the present disclosure, the selected frequency isgreater than 130 Hz.

In an aspect of the present disclosure, the selected frequency is about130 Hz, about 160 Hz, or about 180 Hz and can be any frequency between100-200 Hz.

In an aspect of the present disclosure, the measured HFO evoked in thetarget structure is between 200-450 Hz.

In an aspect of the present disclosure, the ECA includes a resonatingresponse above a predetermined threshold.

If the ECA is below a predetermined threshold, a second LFS is appliedto a second subset of contacts of the multi-contact electrode in adifferent location within the target structure than the contact of themulti-contact electrode.

As an example, one or more chronic electrodes with multiple contacts areimplanted during the intraoperative procedure. A low frequency (<105 Hz)stimulation is applied through one or more contacts. An ECA waveform inLocal Field Potential is recorded and its characteristics (e.g.,amplitude, phase, resonance duration) are determined. The stimulationfrequency range for the optimal response is then computed based on phasespace extracted from ECA. Stimulation is delivered at frequencies withinthis range and the corresponding HFO frequency and/or power is computed.The frequency associated with the maximum HFO power is selected fortreatment. Thus, the system and methods described herein can be employedto fine tune stimulation frequency by processing HFO power and ECA phasespace.

The systems and methods described with reference to FIGS. 5 to 7 mayperiodically be employed to recalibrate the brain stimulationparameters, such as on a predetermined schedule (e.g., once every twentyfour hours, once weekly, etc.). In addition to periodicallyrecalibrating treatment parameters, recalibration may also be performedautonomously to dynamically optimize treatment parameters based onpersonalized and individual physiological changes that occur over time,without the need for direct intervention by a neurosurgeon or treatmentexpert.

Referring particularly to FIG. 6, a method for determining DBSparameters 600 includes applying LFS (step 601), measuring evokedresponse (step 602), determining the phase space for optical stimulationfrequency (step 603), delivering stimulations at several frequencieswithin the suggested range (step 604), estimating bandpower for thespecified high-frequency range (step 605), and selecting the optimizedfrequency providing maximum bandpower (step 606).

Referring to FIG. 7, another method for determining DBS parameters 700includes applying LFS to a contact of a multi-contact electrodeimplanted in a target structure in an individual's brain (step 701).Method 700 includes measuring ECA evoked in the target structure by theLFS (step 702) and determining a range of frequencies for deliveringbrain stimulation within a predetermined range based on a phase spaceextracted from the ECA (step 703). Method 700 includes applyingstimulation frequencies to the contact of the multi-contact electrodewithin the determined range of frequencies (step 704) and measuring HFOevoked in the target structure by the applied stimulation frequencieswithin the determined range (step 705). Method 700 includes determininga frequency evoking HFO above a predetermined threshold (step 706) andselecting the frequency as a treatment frequency for the targetstructure (step 707).

FIG. 8 displays recorded HFO evoked in the STN when a multi-contactelectrode is positioned in the STN and an absence of HFO when themulti-contact electrode is not positioned in the STN. Referring to FIG.8, HFO and resonant evoked compound activity (ECA) are observed duringhigh-frequency DBS only in the STN. In 10 hemispheres, 130 Hzstimulation was performed out- and in-STN to identify and rule out thepossible artifacts that might have been caused by the stimulation or therecording hardware.

FIG. 9 displays recorded HFO and ECA at various HFS frequencies when themulti-contact electrode is positioned in the STN. Referring to FIG. 9,High-frequency stimulations (e.g., 130 Hz, 160 Hz, and 180 Hz) modulateHFO and ECA in different amplitudes.

FIG. 10 displays recorded ECA for a LFS frequency compared with variousHFS frequencies. Referring to FIG. 10, inter-pulse evoked activity showsadaptation only with high-frequency stimulation (e.g., 130 Hz, 160 Hz,and 180 Hz), and not with low frequency stimulation (e.g., 20 Hz).

FIG. 11 illustrates DBS tuning of various HFS frequencies based on aphase of an ECA waveform. Referring to FIG. 11, the DBS can be tuned toprovide maximum modulatory effect based on the phase of ECA waveform.

Each of the following references is incorporated by reference herein inits entirety.

-   Agnesi, F., Connolly, A. T., Baker, K. B., Vitek, J. L., and    Johnson, M. D. (2013). Deep Brain Stimulation Imposes Complex    Informational Lesions. PLoS One 8, 1-11.    doi:10.1371/journal.pone.0074462.-   Ashby, P., Paradiso, G., Saint-Cyr, J. A., Chen, R., Lang, A. E.,    and Lozano, A. M. (2001). Potentials recorded at the scalp by    stimulation near the human subthalamic nucleus. Clin Neurophysiol    112, 431-437. doi:10.1016/S1388-2457(00)00532-0.-   Benabid, A. L., Chabardes, S., Mitrofanis, J., and Pollak, P.    (2009). Deep brain stimulation of the subthalamic nucleus for the    treatment of Parkinson's disease. Lancet Neurol, 67-81.-   Benazzouz, A., Gao, D., Ni, Z., Piallat, B., Bouali-Benazzouz, R.,    and Benabid, A. (2000). Effect of high-frequency stimulation of the    subthalamic nucleus on the neuronal activities of the substantia    nigra pars reticulata and ventrolateral nucleus of the thalamus in    the rat. Neuroscience 99, 289-295.    doi:10.1016/S0306-4522(00)00199-8.-   Berens, P. (2009). CircStat: A MATLAB Toolbox for Circular    Statistics. J Stat Softly 31, 293-295. doi:10.18637/jss.v031.i10.-   Bergman, H., Wichmann, T., Karmon, B., and DeLong, M. R. (1994). The    primate subthalamic nucleus. II. Neuronal activity in the MPTP model    of parkinsonism. J Neurophysiol 72, 507-20.    doi:10.1152/jn.1994.72.2.507.-   Bevan, M. D., Magill, P. J., Terman, D., Bolam, J. P., and    Wilson, C. J. (2002). Move to the rhythm: oscillations in the    subthalamic nucleus-external globus pallidus network. Trends    Neurosci 25, 525-31. doi:10.1016/s0166-2236(02)02235-x.-   Brittain, J.-S., and Brown, P. (2014). Oscillations and the basal    ganglia: Motor control and beyond. Neuroimage 85, 637-647.    doi:10.1016/j.neuroimage.2013.05.084.-   Brown, P., Mazzone, P., Oliviero, A., Altibrandi, M. G., Pilato, F.,    Tonali, P. A., et al. (2004). Effects of stimulation of the    subthalamic area on oscillatory pallidal activity in Parkinson's    disease. Exp Neurol 188, 480-490.    doi:10.1016/j.expneurol.2004.05.009.-   Chu, H.-Y., McIver, E. L., Kovaleski, R. F., Atherton, J. F., and    Bevan, M. D. (2017). Loss of Hyperdirect Pathway Cortico-Subthalamic    Inputs Following Degeneration of Midbrain Dopamine Neurons. Neuron    95, 1306-1318.e5. doi:10.1016/j.neuron.2017.08.038.-   Cleary, D. R., Raslan, A. M., Rubin, J. E., Bahgat, D., Viswanathan,    A., Heinricher, M. M., et al. (2013). Deep brain stimulation    entrains local neuronal firing in human globus pallidus internus. J    Neurophysiol 109, 978-987. doi:10.1152/jn.00420.2012.-   Dostrovsky, J. O., Levy, R., Wu, J. P., Hutchison, W. D., Tasker, R.    R., and Lozano, A. M. (2000). Microstimulation-Induced Inhibition of    Neuronal Firing in Human Globus Pallidus. J Neurophysiol 84,    570-574. doi:10.1152/jn.2000.84.1.570.-   Erwin, B., Jr, M. M., and Baker, K. K. (2000). Mechanisms of deep    brain stimulation and future technical developments. Neurol Res 22,    259-266. doi:10.1080/01616412.2000.11740668.-   Escobar, D., Johnson, L. A., Nebeck, S. D., Zhang, J., Johnson, M.    D., Baker, K. B., et al. (2017). Parkinsonism and Vigilance:    Alteration in neural oscillatory activity and phase-amplitude    coupling in the basal ganglia and motor cortex. J Neurophysiol 118,    jn.00388.2017. doi:10.1152/jn.00388.2017.-   Eusebio, A., Chen, C. C., Lu, C. S., Lee, S. T., Tsai, C. H.,    Limousin, P., et al. (2008). Effects of low-frequency stimulation of    the subthalamic nucleus on movement in Parkinson's disease. Exp    Neurol 209, 125-130. doi:10.1016/j.expneurol.2007.09.007.-   Eusebio, A., Thevathasan, W., Doyle Gaynor, L., Pogosyan, A., Bye,    E., Foltynie, T., et al. (2011). Deep brain stimulation can suppress    pathological synchronisation in parkinsonian patients. J Neurol    Neurosurg Psychiatry 82, 569-573. doi:10.1136/jnnp.2010.217489.-   Filali, M., Hutchison, W. D., Palter, V. N., Lozano, A. M., and    Dostrovsky, J. O. (2004). Stimulation-induced inhibition of neuronal    firing in human subthalamic nucleus. Exp Brain Res 156, 274-281.    doi:10.1007/s00221-003-1784-y.-   Foffani, G., Ardolino, G., Egidi, M., Caputo, E., Bossi, B., and    Priori, A. (2006). Subthalamic oscillatory activities at beta or    higher frequency do not change after high-frequency DBS in    Parkinson's disease. Brain Res Bull 69, 123-130.    doi:10.1016/j.brainresbull 0.2005.11.012.-   Foffani, G., Priori, A., Egidi, M., Rampini, P., Tamma, F., Caputo,    E., et al. (2003). 300-Hz subthalamic oscillations in Parkinson's    disease. Brain 126, 2153-2163. doi:10.1093/brain/awg229.-   Fogelson, N., Kühn, A. A., Silberstein, P., Limousin, P. D., Hariz,    M., Trottenberg, T., et al. (2005). Frequency dependent effects of    subthalamic nucleus stimulation in Parkinson's disease. Neurosci    Lett 382, 5-9. doi:10.1016/j.neulet.2005.02.050.-   Garcia, L., D'Alessandro, G., Bioulac, B., and Hammond, C. (2005a).    High-frequency stimulation in Parkinson's disease: more or less?    Trends Neurosci 28, 209-216. doi: 10.1016/j.tins.2005.02.005.-   Garcia, L., D'Alessandro, G., Fernagut, P., Bioulac, B., and    Hammond, C. (2005b). Impact of High-Frequency Stimulation Parameters    on the Pattern of Discharge of Subthalamic Neurons. J Neurophysiol    94, 3662-3669. doi:10.1152/jn.00496.2005.-   Gmel, G. E., Obradovic, M., Gorman, R. B., Single, P. S., Parker, J.    L., Hamilton, T. J., et al. (2015). A new biomarker for subthalamic    deep brain stimulation for patients with advanced Parkinson's    disease—A pilot study. J Neural Eng 12.    doi:10.1088/1741-2560/12/6/066013.-   Grill, W. M., Snyder, A. N., and Miocinovic, S. (2004). Deep brain    stimulation creates an informational lesion of the stimulated    nucleus. Neuroreport 15, 1137-1140. doi:    10.1097/00001756-200405190-00011.-   Gross, R. E., Krack, P., Rodriguez-Oroz, M. C., Rezai, A. R., and    Benabid, A.-L. (2006). Electrophysiological mapping for the    implantation of deep brain stimulators for Parkinson's disease and    tremor. Mov Disord 21, S259-S283. doi:10.1002/mds.20960.-   Guo, Y., Rubin, J. E., McIntyre, C. C., Vitek, J. L., and Terman, D.    (2008). Thalamocortical Relay Fidelity Varies Across Subthalamic    Nucleus Deep Brain Stimulation Protocols in a Data-Driven    Computational Model. J Neurophysiol 99, 1477-1492.    doi:10.1152/jn.01080.2007.-   Hahn, P. J., Russo, G. S., Hashimoto, T., Miocinovic, S., Xu, W.,    McIntyre, C. C., et al. (2008). Pallidal burst activity during    therapeutic deep brain stimulation. Exp Neurol 211, 243-251.    doi:10.1016/j.expneurol.2008.01.032.-   Hashimoto, T., Elder, C. M., Okun, M. S., Patrick, S. K., and    Vitek, J. L. (2003). Stimulation of the Subthalamic Nucleus Changes    the Firing Pattern of Pallidal Neurons. J Neurosci 23, 1916-1923.    doi:10.1523/JNEUROSCI.23-05-01916.2003.-   Herrington, T. M., Cheng, J. J., and Eskandar, E. N. (2016).    Mechanisms of deep brain stimulation. J Neurophysiol 115, 19-38.    doi:10.1152/jn.00281.2015.-   Hoang, K. B., and Turner, D. A. (2019). The Emerging Role of    Biomarkers in Adaptive Modulation of Clinical Brain Stimulation.    Neurosurgery 85, E430-E439. doi:10.1093/neuros/nyz096.-   Huang, H., Watts, R. L., and Montgomery, E. B. (2014). Effects of    deep brain stimulation frequency on bradykinesia of Parkinson's    disease. Mov Disord 29, 203-206. doi:10.1002/mds.25773.-   Johnson, M. D., Miocinovic, S., McIntyre, C. C., and Vitek, J. L.    (2008). Mechanisms and targets of deep brain stimulation in movement    disorders. Neurotherapeutics 5, 294-308.    doi:10.1016/j.nurt.2008.01.010.-   Kaku, H., Ozturk, M., Viswanathan, A., Shahed, J., Sheth, S. A.,    Kumar, S., et al. (2020). Unsupervised clustering reveals spatially    varying single neuronal firing patterns in the subthalamic nucleus    of patients with Parkinson's disease. Clin Park Relat Disord    3, 100032. doi:10.1016/j.prdoa.2019.100032.-   Kane, A., Hutchison, W. D., Hodaie, M., Lozano, A. M., and    Dostrovsky, J. O. (2009). Dopamine-dependent high-frequency    oscillatory activity in thalamus and subthalamic nucleus of patients    with Parkinson's disease. Neuroreport 20, 1549-1553.    doi:10.1097/WNR.0b013e32833282c8.-   Kent, A. R., Swan, B. D., Brocker, D. T., Turner, D. A., Gross, R.    E., and Grill, W. M. (2015). Measurement of Evoked Potentials During    Thalamic Deep Brain Stimulation. Brain Stimul 8, 42-56.    doi:10.1016/j.brs.2014.09.017.-   Kita, H., and Kitai, S. T. (1991). Intracellular study of rat globus    pallidus neurons: membrane properties and responses to neostriatal,    subthalamic and nigral stimulation. Brain Res 564, 296-305.    doi:10.1016/0006-8993(91)91466-E.-   Kühn, A. A., Kempf, F., Brucke, C., Gaynor Doyle, L.,    Martinez-Torres, I., Pogosyan, A., et al. (2008). High-Frequency    Stimulation of the Subthalamic Nucleus Suppresses Oscillatory    Activity in Patients with Parkinson's Disease in Parallel with    Improvement in Motor Performance. J Neurosci 28, 6165-6173.    doi:10.1523/JNEUROSCI.0282-08.2008.-   Kuhn, A. A., Williams, D., Kupsch, A., Limousin, P., Hariz, M.,    Schneider, G., et al. (2004). Event-related beta desynchronization    in human subthalamic nucleus correlates with motor performance.    Brain 127, 735-746. doi:10.1093/brain/awh106.-   Kuncel, A. M., Cooper, S. E., Wolgamuth, B. R., and Grill, W. M.    (2007). Amplitude- and Frequency-Dependent Changes in Neuronal    Regularity Parallel Changes in Tremor With Thalamic Deep Brain    Stimulation. IEEE Trans Neural Syst Rehabil Eng 15, 190-197.    doi:10.1109/TNSRE.2007.897004.-   Leventhal, D. K., Gage, G. J., Schmidt, R., Pettibone, J. R.,    Case, A. C., and Berke, J. D. (2012). Basal ganglia beta    oscillations accompany cue utilization. Neuron 73, 523-536.    doi:10.1016/j.neuron.2011.11.032.-   Li, Q., Ke, Y., Chan, D. C. W., Qian, Z. M., Yung, K. K. L., Ko, H.,    et al. (2012). Therapeutic Deep Brain Stimulation in Parkinsonian    Rats Directly Influences Motor Cortex. Neuron 76, 1030-1041.    doi:10.1016/j.neuron.2012.09.032.-   Li, S., Arbuthnott, G. W., Jutras, M. J., Goldberg, J. A., and    Jaeger, D. (2007). Resonant Antidromic Cortical Circuit Activation    as a Consequence of High-Frequency Subthalamic Deep-Brain    Stimulation. J Neurophysiol 98, 3525-3537.    doi:10.1152/jn.00808.2007.-   Litvak, V., Eusebio, A., Jha, A., Oostenveld, R., Barnes, G.,    Foltynie, T., et al. (2012). Movement-related changes in local and    long-range synchronization in parkinson's disease revealed by    simultaneous magnetoencephalography and intracranial recordings. J    Neurosci 32, 10541-10553. doi:10.1523/JNEUROSCI.0767-12.2012.-   Lopez-Azcarate, J., Tainta, M., Rodriguez-Oroz, M. C., Valencia, M.,    Gonzalez, R., Guridi, J., et al. (2010). Coupling between beta and    high-frequency activity in the human subthalamic nucleus may be a    pathophysiological mechanism in Parkinson's disease. J Neurosci 30,    6667-6677. doi:10.1523/JNEUROSCI.5459-09.2010.-   Mastro, K. J., and Gittis, A. H. (2015). Striking the right balance:    Cortical modulation of the subthalamic nucleus-globus pallidus    circuit. Neuron 85, 233-235. doi:10.1016/j.neuron.2014.12.062.-   McConnell, G. C., So, R. Q., Hilliard, J. D., Lopomo, P., and    Grill, W. M. (2012). Effective Deep Brain Stimulation Suppresses    Low-Frequency Network Oscillations in the Basal Ganglia by    Regularizing Neural Firing Patterns. J Neurosci 32, 15657-15668.    doi:10.1523/JNEUROSCI.2824-12.2012.-   McIntyre, C. C., and Hahn, P. J. (2010). Network perspectives on the    mechanisms of deep brain stimulation. Neurobiol Dis 38, 329-337.    doi:10.1016/j.nbd.2009.09.022.-   Meissner, W., Leblois, A., Hansel, D., Bioulac, B., Gross, C. E.,    Benazzouz, A., et al. (2005). Subthalamic high frequency stimulation    resets subthalamic firing and reduces abnormal oscillations. Brain    128, 2372-2382. doi:10.1093/brain/awh616.-   Miocinovic, S., de Hemptinne, C., Chen, W., Isbaine, F., Willie, J.    T., Ostrem, J. L., et al. (2018). Cortical Potentials Evoked by    Subthalamic Stimulation Demonstrate a Short Latency Hyperdirect    Pathway in Humans. J Neurosci 38, 9129-9141.    doi:10.1523/JNEUROSCI.1327-18.2018.-   Miocinovic, S., Somayajula, S., Chitnis, S., and Vitek, J. L.    (2013). History, Applications, and Mechanisms of Deep Brain    Stimulation. JAMA Neurol 70, 163. doi:10.1001/2013.jamaneuro1.45.-   Montgomery, Jr, E. B., and Gale, J. T. (2007). “Neurophysiology and    Neurocircuitry,” in Handbook of Parkinson's Disease Neurological    Disease and Therapy., eds. R. Pahwa and K. E. Lyons (New York and    London: CRC Press), 223-238. Available at:    https://books.google.com/books?id=5ObndbjDuRcC.-   Montgomery, E. (2004). Dynamically Coupled, High-Frequency    Reentrant, Nonlinear Oscillators Embedded in Scale-Free Basal    Ganglia-Thalamic-Cortical Networks Mediating Function and Deep Brain    Stimulation Efiects. Nonlinear Stud 11.-   Montgomery, E. B. (2013). “Deep Brain Stimulation: Mechanisms of    Action,” in Neurostimulation (Oxford, UK: John Wiley & Sons, Ltd),    1-19. doi:10.1002/9781118346396.chl.-   Montgomery, E. B., and Gale, J. T. (2008). Mechanisms of action of    deep brain stimulation (DBS). Neurosci Biobehav Rev 32, 388-407.    doi:10.1016/j.neubiorev.2007.06.003.-   Montgomery, E. B., Gale, J. T., and Huang, H. (2005). Methods for    isolating extracellular action potentials and removing stimulus    artifacts from microelectrode recordings of neurons requiring    minimal operator intervention. J Neurosci Methods 144, 107-125.    doi:10.1016/j.jneumeth.2004.10.017.-   Moran, A., Stein, E., Tischler, H., Belelovsky, K., and Bar-Gad, I.    (2011). Dynamic Stereotypic Responses of Basal Ganglia Neurons to    Subthalamic Nucleus High-Frequency Stimulation in the Parkinsonian    Primate. Front Syst Neurosci 5, 1-11. doi:10.3389/fnsys.2011.00021.-   Moro, E., Esselink, R. J. A., Xie, J., Hommel, M., Benabid, A. L.,    and Pollak, P. (2002). The impact on Parkinson's disease of    electrical parameter settings in STN stimulation. Neurology 59,    706-713. doi:10.1212/WNL.59.5.706.-   Orfanidis, S. J. (1995). Introduction to signal processing.    Prentice-Hall, Inc.-   Oswal, A., Brown, P., and Litvak, V. (2013). Synchronized neural    oscillations and the pathophysiology of Parkinson's disease. Curr    Opin Neurol 26, 662-670. doi:10.1097/WCO.0000000000000034.-   Özkurt, T. E., Butz, M., Homburger, M., Elben, S., Vesper, J.,    Wojtecki, L., et al. (2011). High frequency oscillations in the    subthalamic nucleus: A neurophysiological marker of the motor state    in Parkinson's disease. Exp Neurol 229, 324-331.    doi:10.1016/j.expneurol.2011.02.015.-   Ozturk, M., Abosch, A., Francis, D., Wu, J., Jimenez-Shahed, J., and    Ince, N. F. (2019). Distinct subthalamic coupling in the ON state    describes motor performance in Parkinson's disease. Mov Disord.    doi:10.1002/mds.27800.-   Ozturk, M., Kaku, H., Jimenez-Shahed, J., Viswanathan, A., Sheth, S.    A., Kumar, S., et al. (2020a). Subthalamic Single Cell and    Oscillatory Neural Dynamics of a Dyskinetic Medicated Patient With    Parkinson's Disease. Front Neurosci 14, 1-8.    doi:10.3389/fnins.2020.00391.-   Ozturk, M., Telkes, I., Viswanathan, A., Jimenez-shahed, J.,    Tarakad, A., Kumar, S., et al. (2020b). Randomized, double-blind    assessment of LFP versus SUA guidance in STN-DBS lead implantation:    A Pilot Study. Front Neurosci [Accepted].    doi:10.3389/fnins.2020.00611.-   Parker, J. L., Obradovic, M., Hesam Shariati, N., Gorman, R. B.,    Karantonis, D. M., Single, P. S., et al. (2020). Evoked Compound    Action Potentials Reveal Spinal Cord Dorsal Column Neuroanatomy.    Neuromodulation Technol Neural Interface 23, 82-95.    doi:10.1111/ner.12968.-   Priori, A., Foffani, G., Pesenti, A., Tamma, F., Bianchi, A. M.,    Pellegrini, M., et al. (2004). Rhythm-specific pharmacological    modulation of subthalamic activity in Parkinson's disease. Exp    Neurol 189, 369-379. doi:10.1016/j.expneurol.2004.06.001.-   Reese, R., Leblois, A., Steigerwald, F., Potter-Nerger, M., Herzog,    J., Mehdorn, H. M., et al. (2011). Subthalamic deep brain    stimulation increases pallidal firing rate and regularity. Exp    Neurol 229, 517-521. doi:10.1016/j.expneurol.2011.01.020.-   Rizzone, M., Lanotte, M., Bergamasco, B., Tavella, A., Torre, E.,    Faccani, G., et al. (2001). Deep brain stimulation of the    subthalamic nucleus in Parkinson's disease: effects of variation in    stimulation parameters. J Neurol Neurosurg Psychiatry 71, 215-9.    doi:10.1136/jnnp.71.2.215.-   Rubin, J. E., and Terman, D. (2004). High Frequency Stimulation of    the Subthalamic Nucleus Eliminates Pathological Thalamic Rhythmicity    in a Computational Model. J Comput Neurosci 16, 211-235.    doi:10.1023/BJCNS.0000025686.47117.67.-   Saenger, V. M., Kahan, J., Foltynie, T., Friston, K., Aziz, T. Z.,    Green, A. L., et al. (2017). Uncovering the underlying mechanisms    and whole-brain dynamics of deep brain stimulation for Parkinson's    disease. Sci Rep 7, 9882. doi:10.1038/s41598-017-10003-y.-   Santaniello, S., McCarthy, M. M., Montgomery, E. B., Gale, J. T.,    Kopell, N., and Sarma, S. V. (2015). Therapeutic mechanisms of    high-frequency stimulation in Parkinson's disease and neural    restoration via loop-based reinforcement. Proc Natl Acad Sci 112,    E586-E595. doi:10.1073/pnas.1406549111.-   Sharott, A., Gulberti, A., Zittel, S., Tudor Jones, A. A., Fickel,    U., Munchau, A., et al. (2014). Activity Parameters of Subthalamic    Nucleus Neurons Selectively Predict Motor Symptom Severity in    Parkinson's Disease. J Neurosci 34, 6273-6285.    doi:10.1523/jneurosci.1803-13.2014.-   Sinclair, N. C., McDermott, H. J., Bulluss, K. J., Fallon, J. B.,    Perera, T., Xu, S. S., et al. (2018). Subthalamic nucleus deep brain    stimulation evokes resonant neural activity. Ann Neurol 83,    1027-1031. doi:10.1002/ana.25234.-   Sinclair, N. C., McDermott, H. J., Fallon, J. B., Perera, T., Brown,    P., Bulluss, K. J., et al. (2019). Deep brain stimulation for    Parkinson's disease modulates high-frequency evoked and spontaneous    neural activity. Neurobiol Dis 130, 104522.    doi:10.1016/j.nbd.2019.104522.-   Soares, J., Kliem, M. A., Betarbet, R., Greenamyre, J. T., Yamamoto,    B., and Wichmann, T. (2004). Role of External Pallidal Segment in    Primate Parkinsonism: Comparison of the Effects of    1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Induced Parkinsonism    and Lesions of the External Pallidal Segment. J Neurosci 24,    6417-6426. doi:10.1523/jneurosci.0836-04.2004.-   Stefani, A., Fedele, E., Vitek, J., Pierantozzi, M., Galati, S.,    Marzetti, S., et al. (2011). The clinical efficacy of L-DOPA and    STN-DBS share a common marker: Reduced GABA content in the motor    thalamus. Cell Death Dis 2, 1-9. doi:10.1038/cddis.2011.35.-   Stypulkowski, P. H., Giftakis, J. E., and Billstrom, T. M. (2011).    Development of a Large Animal Model for Investigation of Deep Brain    Stimulation for Epilepsy. Stereotact Funct Neurosurg 89, 111-122.    doi:10.1159/000323343.-   Swann, N. C., de Hemptinne, C., Miocinovic, S., Qasim, S., Wang, S.    S., Ziman, N., et al. (2016). Gamma Oscillations in the Hyperkinetic    State Detected with Chronic Human Brain Recordings in Parkinson's    Disease. J Neurosci 36, 6445-6458.    doi:10.1523/JNEUROSCI.1128-16.2016.-   Telkes, I., Jimenez-Shahed, J., Viswanathan, A., Abosch, A., and    Ince, N. F. (2016). Prediction of STN-DBS electrode implantation    track in Parkinson's disease by using local field potentials. Front    Neurosci 10, 1-16. doi:10.3389/fnins.2016.00198.-   Thompson, J. A., Tekriwal, A., Felsen, G., Ozturk, M., Telkes, I.,    Wu, J., et al. (2018). Sleep patterns in Parkinson's disease: direct    recordings from the subthalamic nucleus. J Neurol Neurosurg    Psychiatry 89, 95-104. doi: 10.1136/j nnp-2017-316115.-   Urrestarazu, E., Iriarte, J., Alegre, M., Clavero, P.,    Rodriguez-Oroz, M. C., Guridi, J., et al. (2009). Beta activity in    the subthalamic nucleus during sleep in patients with Parkinson's    disease. Mov Disord 24, 254-260. doi:10.1002/mds.22351.-   van Wijk, B. C. M., Beudel, M., Jha, A., Oswal, A., Foltynie, T.,    Hariz, M. I., et al. (2016). Subthalamic nucleus phase-amplitude    coupling correlates with motor impairment in Parkinson's disease.    Clin Neurophysiol 127, 2010-2019. doi:10.1016/j.clinph.2016.01.015.-   Weinberger, M., Mahant, N., Hutchison, W. D., Lozano, A. M., Moro,    E., Hodaie, M., et al. (2006). Beta Oscillatory Activity in the    Subthalamic Nucleus and Its Relation to Dopaminergic Response in    Parkinson's Disease. J Neurophysiol 96, 3248-3256. doi:10.1152/j    n.00697.2006.-   Welter, M.-L., Houeto, J.-L., Bonnet, A.-M., Bejjani, P.-B.,    Mesnage, V., Dormont, D., et al. (2004). Effects of High-Frequency    Stimulation on Subthalamic Neuronal Activity in Parkinsonian    Patients. Arch Neurol 61, 89. doi:10.1001/archneur.61.1.89.-   Wichmann, T., and DeLong, M. R. (2006). “Basal ganglia discharge    abnormalities in Parkinson's disease,” in Parkinson's Disease and    Related Disorders (Vienna: Springer Vienna), 21-25.    doi:10.1007/978-3-211-45295-0_5.-   Xu, W., Russo, G. S., Hashimoto, T., Zhang, J., and Vitek, J. L.    (2008). Subthalamic Nucleus Stimulation Modulates Thalamic Neuronal    Activity. J Neurosci 28, 11916-11924.    doi:10.1523/JNEUROSCI.2027-08.2008.-   Youngerman, B. E., Chan, A. K., Mikell, C. B., McKhann, G. M., and    Sheth, S. A. (2016). A decade of emerging indications: deep brain    stimulation in the United States. J Neurosurg 125, 461-471.    doi:10.3171/2015.7.JNS142599.-   Zhou, A., Johnson, B. C., and Muller, R. (2018). Toward true    closed-loop neuromodulation: artifact-free recording during    stimulation. Curr Opin Neurobiol 50, 119-127.    doi:10.1016/j.conb.2018.01.012.-   Zhuang, Q. X., Li, G. Y., Li, B., Zhang, C. Z., Zhang, X. Y., Xi,    K., et al. (2018). Regularizing firing patterns of rat subthalamic    neurons ameliorates parkinsonian motor deficits. J Clin Invest 128,    5413-5427. doi:10.1172/JCI99986.

It will be understood that various modifications may be made to theaspects and features disclosed herein. Therefore, the above descriptionshould not be construed as limiting, but merely as exemplifications ofvarious aspects and features. Those skilled in the art will envisionother modifications within the scope and spirit of the claims appendedthereto.

What is claimed is:
 1. A method of determining brain stimulationparameters, the method comprising: applying Low Frequency Stimulation(LFS) to a subset of contacts of a multi-contact electrode implanted ina target structure in an individual's brain; measuring Evoked CompoundActivity (ECA) evoked in the target structure by the LFS; determining arange of frequencies for delivering brain stimulation within apredetermined range based on a phase space extracted from the ECA;applying stimulation frequencies to the subset of contacts of themulti-contact electrode within the determined range of frequencies;measuring High Frequency Oscillations (HFO) evoked in the targetstructure by the applied stimulation frequencies within the determinedrange; determining a frequency evoking HFO above a predeterminedthreshold; and selecting the frequency as a treatment frequency for thetarget structure.
 2. The method of claim 1, wherein the LFS is less than100 Hz.
 3. The method of claim 1, wherein the selected frequency isgreater than 100 Hz.
 4. The method of claim 1, wherein the selectedfrequency is about 130 Hz, about 160 Hz, or about 180 Hz.
 5. The methodof claim 1, wherein the measured HFO evoked in the target structure isfrom 200 Hz to 450 Hz.
 6. The method of claim 1, wherein the ECAincludes a resonating response above a predetermined threshold.
 7. Themethod of claim 1, wherein if the ECA is below a predeterminedthreshold, applying a second LFS to a second subset of contacts of themulti-contact electrode in a different location within the targetstructure than the subset of contacts of the multi-contact electrode. 8.The method of claim 1, wherein the multi-contact electrode is configuredfor Deep Brain Stimulation (DB S) of the target structure.
 9. The methodof claim 1, wherein the target structure is the Subthalamic nucleus(STN).
 10. The method of claim 1, wherein the individual has Parkinson'sDisease (PD).
 11. A system for determining deep brain stimulationparameters, comprising: at least one multi-contact electrode configuredfor implanting in a target structure in an individuals' brain; astimulating device in electrical communication with the at least onemulti-contact electrode, the stimulating device configured to apply LowFrequency Stimulation (LFS) or High Frequency Stimulation (HF S) to theat least one multi-contact electrode; a recording device configured torecord at least one of Evoked Compound Activity (ECA) evoked in thetarget structure by the LFS and High Frequency Oscillations (HFO) evokedin the target structure by the HFS; a signal processing unit incommunication with the recording device, the signal processing unitconfigured to determine a range of frequencies for delivering brainstimulation within a predetermined range based on a phase spaceextracted from the ECA, the signal processing unit configured to analyzeHigh Frequency Oscillations (HFO) evoked in the target structure by theapplied stimulation frequencies within the determined range; and aparameter optimization unit configured to determine a frequency evokingHFO above a predetermined threshold, and to select the frequency as atreatment frequency for the target structure.
 12. The system of claim11, wherein the stimulating device is configured to selectively applythe LFS or HFS to a subset of contacts of one multi-contact electrode ofthe plurality of multi-contact electrodes.
 13. The system of claim 11,wherein at least one of the stimulating device, the recording device,the signal processing unit, and the parameter optimization unit areimplanted in the individual's chest.
 14. The system of claim 13, furtherincluding an input/output (I/O) unit in electrical communication withthe stimulating device, the recording device, the signal processingunit, and the parameter optimization unit.
 15. The method of claim 11,wherein the LFS is less than 50 Hz.
 16. The method of claim 11, whereinthe selected frequency is greater than 130 Hz.
 17. The method of claim11, wherein the selected frequency is about 130 Hz, about 160 Hz, orabout 180 Hz.
 18. The method of claim 11, wherein the HFO evoked in thetarget structure is from 200 Hz to 450 Hz.
 19. The method of claim 11,wherein the multi-contact electrode is configured for Deep BrainStimulation (DB S) of the target structure.
 20. The method of claim 11,wherein the target structure is the Subthalamic nucleus (STN).